Born somewhere in the Russian state of Kiev in the late 15th century, Armand (at this time called Andrei) becomes an icon painter in a monastery. He is forcefully taken out of this life of prayer and devotion by slave traders, who take him to Constantinople and then to Venice, where he is destined to work in a brothel. Soon after his arrival in Venice he is purchased by the vampire Marius de Romanus (whose life story is told in 2001's Blood and Gold), who names him Amadeo.

In Venice, Marius lives the extravagant life of a respected Renaissance painter, and mentors many boys who serve as his apprentices. Marius provides his apprentices with education, shelter, food, and he assists them in finding respectable positions once they are grown. Life in Marius' villa is a stark contrast to the poverty, hunger and disease described elsewhere in the city. Over time, Amadeo's relationship to Marius develops and they become much closer than Marius is with any of the other boys. In addition to developing a sexual relationship, Amadeo sleeps in Marius' bed, is privy to special privileges, and becomes something of a 'head boy' in the household. Still, Marius maintains strict control over Amadeo, and expects industriousness from him in all things.

When Amadeo comes of age (the book is not specific, but he is most likely 15 or 16 at this point), Marius begins Amadeo's education in sexuality and coupling. He takes Amadeo to a brothel, where Amadeo remains for several days. Amadeo later visits a male brothel for several days, and while there makes several observations about the difference in sexual activities with the different genders. There is a distinct bisexuality to Amadeo's nature, as he enjoys activity with either sex. He later has a brief affair with an Englishman called Lord Harlech. Harlech becomes obsessed with Amadeo, but his love is not returned. During this period, Amadeo also befriends Bianca Solderini, a wealthy debutante and courtesan whose primary role in life seems to be to throw nightly parties. Amadeo ultimately seduces the willing Bianca.

Marius eventually divulges his vampire nature to Amadeo, who almost immediately begins asking to be made a vampire. Marius shows Amadeo some of what it means to be immortal, and allows him to join him in the hunt on several occasions. He tells Amadeo that they must always focus on killing evildoers. They assist Bianca by murdering her kinsmen who force her to poison those from whom they have borrowed money.

Eventually, on a night when Marius is out of the country, Lord Harlech breaks into Marius's palazzo and attacks Amadeo, murdering two apprentices in the process. Amadeo kills Harlech, but not before the Englishman wounds him with a poisoned sword. Amadeo falls critically ill, and over several days falls into fever and delusions. Upon returning and finding Amadeo on his deathbed, Marius heals Amadeo's external wounds, cleans and grooms him, then gives him the Dark Gift, turning him into a vampire.

Marius sets out to train Amadeo, and sets up a coffin in a secret basement with his own. Marius retains high expectations of Amadeo, and forces him to continue his education in the arts. Amadeo's transition to vampire is relatively easy for him, although the Dark Gift brings about nightmares of his childhood. Marius and Amadeo return to Russia, where Amadeo visits his old school and home. He finds his elderly mother and father there, reveals that he is alive, and says farewell to them, leaving them with all the money and jewels he has with him. This is generally a happy reunion, as Amadeo is able to let go of his mortal background and his parents are able to see that their beloved son is alive (so to speak) and thriving. Though this reunion allows Amadeo to let go of his mortal background, discovering that his father is alive (Amadeo believed he was dead) and a drunkard hurts him deeply.

Shortly after returning to Venice, the vampire Santino and his coven (the "Children of Darkness") attack Marius' home, kidnap Amadeo and the apprentices, and burn the villa. Marius is burned and thought to be destroyed; his boys are taken to a bonfire that the coven has created and thrown in one by one as Amadeo watches. Santino spares Amadeo and educates him in the laws of the Coven. Amadeo later goes to Paris, changes his name to Armand, and creates his own coven under the Cimetière des Innocents, which Lestat would years later drastically impact thus resulting in the creation of the Théâtre des Vampires (featured in the earlier novel Interview with the Vampire).

Armand also shares with David his version of some of the events recounted by Louis de Pointe du Lac in Interview with the Vampire: the end of the Théâtre des Vampires and the time that Armand and Louis shared together. The book also chronicles Armand's feelings about several of the major vampire characters from the previous books. It is also revealed that Armand thinks he saw Bianca in Paris in the 19th century, and has wondered ever since if Marius made her a vampire.

In the final segment of the book, Armand explains what occurred to him after the final chapters of Memnoch the Devil. At the end of Memnoch the Devil, Armand rushes into the open daylight and appears to be destroyed in a conflagration. Armand explains to David that by some means beyond his understanding he survived, and ended up on a rooftop in a stairwell protected from further exposure to the sun. However, he is badly burned and unable to move or fully function. While in this delirious state, he makes a mental connection to two children in a nearby apartment - Sybelle and Benji. The connection is forged through Sybelle's constant piano playing.

Eventually, Armand is able to reach out to the children and lead them to him. They believe he is an angel, but are moderately unsurprised when Armand divulges his true nature to them. Armand cannot hunt, so the two agree to trick a drug dealer up to the apartment so that Armand may feed on him. The plan works, and ultimately Armand is fully healed. He becomes friends with Sybelle and Benji and ultimately falls in love with them, showing to a certain degree a lolita complex. He shares his wealth with them without limit, mirroring the relationship Marius had with him to a certain degree.

Armand brings them to see Lestat, which he has some concerns about since vampires are traditionally not safe for mortals to be around. After trying to wake Lestat from his catatonic state, Armand returns to Marius's house to discover that Marius has given Benji and Sybelle the Dark Gift. Armand is at first furious at Marius because he wanted Sybelle and Benji to have full, mortal lives. The fact that Benji is ecstatic about the prospect of eternal life, only serves to fuel his anger. Marius explains to Armand that he did it since Armand never could without the two coming to hate him for it. Marius is willing to take the burden of Sybelle and Benji's eventual anger.

Like many of Rice's novels, The Vampire Armand deals with various aspects of human sexuality. Although the vampires themselves can not procreate, they do have a sexuality about them and practice their version of homosexuality, bisexuality and sadomasochism. Such seems to be a recurrent theme throughout Anne Rice's books, as well as pederasty, as Armand is just past puberty when Marius first takes him as a lover. Another example, is instances where Armand is visiting brothels, and gives a detailed description of the "pleasure" he obtained at the hands of "beautiful boys". The mortal human characters are also largely portrayed as bisexual, both in the medieval and modern day periods covered in the novel.

Sex is used throughout the novel as both a reward and a punishment, and to a large extent drives some of the conflict between characters. An example of a such a relationship, is that between Marius and Armand. There are also recurrent themes of BDSM within the novel, as well as disambiguous references to "sleeping beauty" awakening from her slumber, perhaps a reference to Rice's The Sleeping Beauty Quartet.